To
test this management strategy, Dr Grant and colleagues conducted a pragmatic
cluster-randomised trial in which the clusters were primary healthcare clinics
in South Africa. Individuals were
eligible if they were HIV-positive adults with CD4 cell counts of 150 cells/mm3
or less, who had not used ART in the past six months or TB treatment in the
last three months and who had no danger signs requiring immediate hospital
referral.
In
intervention clinics the study staff enrolled patients and facilitated the
study algorithm working with clinic staff. They also took a single sputum
specimen for M tuberculosis culture
and a urine specimen was stored for later culture at the end of the study.
Subsequent management was done by clinic staff. In the control clinics, the
staff enrolled patients, stored a urine specimen, and all of the management and
care was done by clinic staff according to their usual practices.
Study
staff reviewed case notes at two and six months, and there was a 6-month study
visit to determine vital status, TB treatment start dates, ART treatment start
dates and important events such as hospitalisation.
The
primary outcome was all-cause mortality at six months, and there were a number
of secondary outcomes including:
- Hospitalisation in first six months
- Time from enrolment to ART start
- Retention in care at six months
- Serious adverse events and severe adverse events in study-defined
categories
- Diagnostic cost per TB case detected
- Cost effectiveness.
The
researchers made some critical assumptions when calculating the sample size
needed for the study. They assumed that
60% of early deaths on ART were due to TB and that two-thirds of these would be
preventable by earlier TB treatment. But they also thought that by removing the
need for TB investigation they would be able to accelerate the start of ART in
all participants, which would lead to an additional reduction in mortality. So
they concluded that with 12 clusters per arm, the study would be well-powered
to reliably assess a 40% reduction in mortality.
A
total of 3053 people were assigned to the study, but 30 had to be excluded,
leaving 1507 participants in the intervention arm and 1516 in the control arm.
The study arms were quite well balanced. Just slightly more than half of the
participants were women with a median age of 38. The median CD4 count was 74
cells/mm3 and about 20% had a body mass index (BMI) of less than
18.5. Most people reported one or more symptoms consistent with TB.
In
the intervention clinics, use of the triage algorithm led to 46% of people
being assigned a high probability of TB, 32% a medium probability and 23% a low
probability. This resulted in 62% of people in the intervention arm starting TB
treatment, compared with 11% in the control arm.
Retention
in the study was good and vital status could be determined in about 98% of the
study participants at six months in each arm.
As
for the primary outcome of mortality, in the intervention arm the mortality
rate was 19 per 100 person-years compared with 21.6 in the control arm, which
was not significantly different.
Data
on two secondary outcomes were presented. 13% of the intervention arm
participants were hospitalised in the first six months, compared to 10% in the
control arm, which again was not a significant difference.
More
importantly, in the intervention arm, 66% of the people had started ART within 30
days, while in the control arm 73% had started. While this is not a great
difference, it was the opposite of what the investigators had expected to
happen.
In
the high probability category, 11.5% of people had microbiologically confirmed
TB, compared with 4.4% in the medium and 1.8% in the low probability categories. Of these, 83% started TB treatment within
seven days.
"We
looked at the mortality rates among people in both arms of the study who had
not yet started ART and in the first 14 days after enrolment, the mortality
rate was 29 per 100 person-years, rising to 47 per hundred person-years amongst
those on treatment for 15 days or more," Grant said. "So this
certainly suggests that delay in starting antiretroviral therapy is associated
with worse outcomes."
"Our results
support existing WHO policy on empirical TB treatment, which is not to extend
empirical TB treatment widely in ambulatory patients," she continued. Grant
added that more work is needed to refine
the care package for people with advanced HIV disease at high TB risk,
including the development of a better point-of-care TB diagnostic test.
"More
broadly, what we need is wider HIV testing and earlier ART initiation so that
people do not reach this stage of advanced disease where they are at such high
risk," she concluded.